EP0179254B1 - Acides dihydro-4,5 oxo-4[(trans-phényl-2 cyclopropyl)amino]-2 furanecarboxyliques-3 et leurs dérivés - Google Patents

Acides dihydro-4,5 oxo-4[(trans-phényl-2 cyclopropyl)amino]-2 furanecarboxyliques-3 et leurs dérivés Download PDF

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Publication number
EP0179254B1
EP0179254B1 EP85111574A EP85111574A EP0179254B1 EP 0179254 B1 EP0179254 B1 EP 0179254B1 EP 85111574 A EP85111574 A EP 85111574A EP 85111574 A EP85111574 A EP 85111574A EP 0179254 B1 EP0179254 B1 EP 0179254B1
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EP
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Prior art keywords
trans
amino
oxo
dihydro
compound
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
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EP85111574A
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German (de)
English (en)
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EP0179254A1 (fr
Inventor
Vassil Stefano Georgiev
Robert Allan Mack
Clyde Richard Kinsolving
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Pennwalt Corp
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Pennwalt Corp
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Priority to AT85111574T priority Critical patent/ATE41773T1/de
Publication of EP0179254A1 publication Critical patent/EP0179254A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • This invention relates generally to 2-[(N-substituted)amino]-4,5-dihydro-4-oxo-3-furancarboxylic acids and more specifically to 4,5-dihydro-4-oxo-2-[(2-trans-phenylcyclopropyl)amino]-3-furancarbox- ylic acids and derivatives thereof.
  • the compounds of the invention are carboxylic acids and acid derivatives including alkali metal salts of the acid, esters formed from lower alkyl alcohols.
  • R 1 in the general formula include phenyl and substituted phenyl wherein the term "substituted phenyl” as used herein refers to phenyl substituted with lower alkyl and/or halogen (chlorine, fluorine, bromine, iodine), preferably chlorine.
  • the compounds of the invention can be prepared as illustrated in the following diagram which involves a base-catalyzed cyclocondensation of C 1 ⁇ C 8 4-chloroacetoacetate I with an appropriate trans-phenylcyclopropyl isocyanate 11 to provide the esters lll.
  • Alkaline hydrolysis of esters III gives the corresponding free acids IV.
  • treatment of the free acids IV with sodium carbonate (or another alkali metal carbonate) gives the salts VII.
  • Compound 2 was prepared by a similar process to that described in Example 1 with trans-4-chlorophe- nylcyclopropylisocyanate being reacted with ethyl 4-chloroacetoacetate.
  • Compound 3 was prepared by a similar process to that described in Example 1 with trans-4-(methylphenyl)cyclopropylisocyanate being reacted with ethyl 4-chloroacetoacetate.
  • the compound 4 (5.05 grams, 19.5 mmol), was neutralized with sodium carbonate (2.56 grams, 24.2 mmol) in 150 ml water. The solution was warmed to 50 ° C, then filtered and concentrated to 50 ml under vacuum. The addition of a small amount of ethanol caused a rapid crystallization of the sodium salt 7. Recrystallization from water provided 4.66 grams of pure sodium salt as the monohydrate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Furan Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)

Claims (11)

1. Procédé de production d'un acide 4,5-dihydro-4-oxo-2-[(2-trans-phénylcyclopropyl)amino]-3-furanne-carboxylique ou d'un de ses dérivés, répodant à la formule générale:
Figure imgb0011
dans laquelle R est choisi entre un groupe hydroxy, un groupe alkoxy ayant 1 à 8 atomes de carbone et un groupe O-métal alcalin, et dans laquelle R1 est choisi entre un groupe phényle et un groupe phényle substitué; caractérisé en ce qu'il consiste à préparer les dérivés du type ester, dans lesquels R représente un groupe alkoxy ayant 1 à 8 atomes de carbone, par une cyclocondensation, catalysée par une base, d'un 4-chloroacéto-acétate d'alkyle en C1 à C8 avec un isocyanate de trans-phénylcyclopropyle de formule:
Figure imgb0012
dans laquelle R1 répond à la définition précitée, à préparer l'acide libre dans lequel R représente un groupe hydroxy, par hydrolyse alcaline des dérivés du type ester et à préparer les dérivés du type sel, dans lesquels R représente un groupe O-métal alcalin, par réaction de l'acide libre avec un carbonate de métal alcalin.
2. Procédé suivant la revendication 1, destiné à la production d'un composé dans lequel R représente un groupe hydroxy.
3. Procédé suivant la revendication 1, destiné à la production d'un composé dans lequel R représente un groupe alkoxy ayant 1 à 8 atomes de carbone.
4. Procédé suivant la revendication 1, destiné à la production d'un composé dans lequel R représente un groupe O-métal alcalin.
5. Procédé suivant la revendication 1, destiné à la production de l'ester éthylique de l'acide 4,5-di- hydro-4-oxo-2-[(trans-phénylcyclopropyl)-amino]-3-furanne-carboxylique.
6. Procédé suivant la revendication 1, destiné à la production de l'ester éthylique de l'acide 4,5-di- hydro-4-oxo-2-[[2-trans-(4-chlorophényl)cyclopropyl]-amino]-3-furanne-carboxylique.
7. Procédé suivant la revendication 1, destiné à la production de l'ester éthylique de l'acide 4,5-di- hydro-4-oxo-2-[[2-trans-(4-méthylphényl)cyclopropyl]-amino]-3-furanne-carboxylique.
8. Procédé suivant la revendication 1, destiné à la production de l'acide 4,5-dihydro-4-oxo-2-[(2- trans-phénylcyclopropyl)amino]-3-furanne-corboxylique.
9. Procédé suivant la revendication 1, destiné à la production de l'acide 4,5-dihydro-4-oxo-2-[[2- trans-(4-méthylphényl)cyclopropyl]-amino]-3-furanne-carboxylique.
10. Prodédé suivant la revendication 1, destiné à la production de l'acide 4,5-dihydro-4-oxo-2-[[2- trans-(4-chlorophényl)cyclopropyl]-amino]-3-furanne-carboxylique.
11. Procédé suivant la revendication 1, destiné à la production du sel de sodium de l'acide 4,5-dihydro-4-oxo-2-[(2-trans-phénylcyclopropyl)-amino]-3-furanne-carboxylique.
EP85111574A 1984-09-24 1985-09-13 Acides dihydro-4,5 oxo-4[(trans-phényl-2 cyclopropyl)amino]-2 furanecarboxyliques-3 et leurs dérivés Expired EP0179254B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT85111574T ATE41773T1 (de) 1984-09-24 1985-09-13 4,5-dihydro-4-oxo-2((2-transphenylcyclopropyl)amino>-3-furancarbonsaeuren und derivate davon.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US653254 1984-09-24
US06/653,254 US4614810A (en) 1984-09-24 1984-09-24 4,5-dihydro-4-oxo-2-[(2-trans-phenylcyclopropyl)amino]-3-furancarboxylic acids and derivatives thereof

Publications (2)

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EP0179254A1 EP0179254A1 (fr) 1986-04-30
EP0179254B1 true EP0179254B1 (fr) 1989-03-29

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Country Status (15)

Country Link
US (1) US4614810A (fr)
EP (1) EP0179254B1 (fr)
JP (1) JPS6178778A (fr)
KR (1) KR860002489A (fr)
AT (1) ATE41773T1 (fr)
AU (1) AU570572B2 (fr)
CA (1) CA1240687A (fr)
DE (1) DE3569112D1 (fr)
DK (1) DK429585A (fr)
FI (1) FI853648A7 (fr)
IL (1) IL76194A (fr)
NO (1) NO853737L (fr)
NZ (1) NZ213190A (fr)
PH (1) PH21253A (fr)
ZA (1) ZA856907B (fr)

Families Citing this family (13)

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ZA912138B (en) * 1990-03-26 1991-12-24 Schering Corp Bcrf1 antagonists for treating epstein-barr virus infections
US7186735B2 (en) * 2002-08-07 2007-03-06 Sanofi-Aventis Deutschland Gmbh Acylated arylcycloalkylamines and their use as pharmaceuticals
EP1388535A1 (fr) * 2002-08-07 2004-02-11 Aventis Pharma Deutschland GmbH Arylcycloalkylamines acylés et leurs utilisations comme produits pharmaceutiques
EP3105219B9 (fr) 2014-02-13 2018-10-03 Incyte Corporation Cyclopropylamines en tant qu'inhibiteurs de lsd1
US9527835B2 (en) 2014-02-13 2016-12-27 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
SI3105218T1 (sl) * 2014-02-13 2019-11-29 Incyte Corp Ciklopropilamini kot inhibitorji LSD1
MX373103B (es) 2014-02-13 2020-04-17 Incyte Holdings Corp Ciclopropilaminas como inhibidores de desmetilasa específica de lisina 1 (lsd1).
TWI687419B (zh) 2014-07-10 2020-03-11 美商英塞特公司 作為ｌｓｄ１抑制劑之咪唑并吡啶及咪唑并吡嗪
TW201613925A (en) 2014-07-10 2016-04-16 Incyte Corp Imidazopyrazines as LSD1 inhibitors
WO2016007722A1 (fr) 2014-07-10 2016-01-14 Incyte Corporation Triazolopyridines et triazolopyrazines utilisables comme inhibiteurs de lsd1
EP3277689B1 (fr) 2015-04-03 2019-09-04 Incyte Corporation Composés hétérocycliques utilisés en tant qu'inhibiteurs de lsd1
LT3334709T (lt) 2015-08-12 2025-03-10 Incyte Holdings Corporation Lsd1 inhibitoriaus druskos
WO2020047198A1 (fr) 2018-08-31 2020-03-05 Incyte Corporation Sels d'un inhibiteur de lsd1 et leurs procédés de préparation

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Publication number Priority date Publication date Assignee Title
GB1210848A (en) * 1968-07-01 1970-11-04 Mcneilab Inc 2-imino-methyleneimines
US4244958A (en) * 1979-05-10 1981-01-13 American Home Products Corporation Hypolipidemic derivatives of 4,5-dihydro-4-oxofuran-2-carboxylic acid
DE3301107A1 (de) * 1983-01-14 1984-07-19 Ozaki, Shoichiro, Ehime Neue 1-(n-substituierte carbamoyl)-5-fluorouracil-derivate und krebshemmende mittel, in denen sie als aktive bestandteile enthalten sind

Also Published As

Publication number Publication date
DE3569112D1 (en) 1989-05-03
FI853648L (fi) 1986-03-25
FI853648A7 (fi) 1986-03-25
US4614810A (en) 1986-09-30
EP0179254A1 (fr) 1986-04-30
NO853737L (no) 1986-03-25
FI853648A0 (fi) 1985-09-23
ATE41773T1 (de) 1989-04-15
DK429585A (da) 1986-03-25
AU570572B2 (en) 1988-03-17
JPS6178778A (ja) 1986-04-22
DK429585D0 (da) 1985-09-23
NZ213190A (en) 1988-04-29
IL76194A (en) 1988-06-30
AU4629885A (en) 1986-04-10
CA1240687A (fr) 1988-08-16
PH21253A (en) 1987-08-31
ZA856907B (en) 1987-03-25
IL76194A0 (en) 1985-12-31
KR860002489A (ko) 1986-04-26

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